The emergence of the HIV/acquired immunodeficiency syndrome pandemic is among the most significant health problems arising worldwide in the last thirty years. It has led to the development of antiretroviral treatments able to stop the progression of infection and reducing mortality (De Cock K, Crowley S P, Lo Y R, Granich R M, Williams B G. Boletin de la Organizacióon Mundial de la Salud 2009; 87: 488-488). UNAIDS estimated in its 2008 report that there were 33 million people infected with HIV, 2.7 million of them were new cases detected in that year. It is estimated that 67% of global infections occur in sub-Saharan Africa (Report on the global AIDS epidemic 2008. Geneva, UNAIDS). According to a bulletin issued by the World Health Organization in 2009, there are two major tendencies worldwide: the total affection of the sub-Saharan African population and the concentration of infection in specific risk groups throughout the rest of the world, respectively. (De Cock K, Crowley S P, Lo Y R, Granich R M, Williams B G 2009. Boletin de la Organización Mundial de la Salud 87: 488-489).
The annual incidence of HIV infection peaked in the middle of the 1990's (Bongaarts J, Buettner T, Heilig G, Pelletier F. Popul Dev Rev 2008; 34: 199-224). However, the total number of HIV-infected people continues to increase in Africa, due to a persistently high incidence of the virus and the population growth rate (De Cock K, Crowley S P, Lo Y R, Granich R M, Williams B G 2009. Boletin de la Organización Mundial de la Salud 87: 488-489).
The appearance of HIV variants that are resistant against the currently available anti-HIV drugs and the poor adherence to treatment by patients remain as the main causes for therapeutic failure. Viral resistance was observed since the start of antiretroviral monotherapy, leading to the appearance of the combined anti-HIV therapy with two or more anti-HIV agents, each of them with a different mechanism of action. Morbidity and mortality rates significantly decreased among treated patients with the introduction of the highly active antiretroviral therapy (HAART). This therapy combines nucleosidic and non-nucleosidic reverse transcriptase inhibitors and protease (PR) inhibitors. Nevertheless, the multi-drug therapy does not eliminate HIV completely, with long-term treatment generally resulting in resistance to several drugs. Half of the patients receiving combined anti-HIV therapy do not completely respond to treatment, mainly due to viral resistance to one or more of the drugs applied. Additionally, viral resistance has been detected in recently infected patients, significantly limiting the therapeutic options for those patients.
The success of combined anti-HIV therapy gave an outlook on a possible eradication of the virus. However, existence of viral reservoirs has been described in latently infected cells and also in tissues where the virus persists regardless of therapy. It has been estimated that more than 70 years of continuous treatment are required to eradicate viral reservoirs, a fact considered improbable since therapy implies secondary effects and occasionally fatal metabolic complications such as lactic acidosis, diabetes mellitus, lipodystrophy, pancreatitis and others (Iglesias E 2009. Biotecnologia Aplicada 26: 189-194).
The adherence to HIV antiretroviral therapy is one of the most debatable issues regarding HAART, and specifically PR (protease) inhibitors, due to the fast appearance of viral resistance if the drugs are irregularly taken or the treatment is interrupted. There are several factors for non-adherence to treatment, including drug intolerance, complex administration regimes, therapeutic failure, drug interactions, social-economical problems, and others.
Combination therapy delays progression to AIDS, but does not cure the infected patients (Marsden M D, Zack J A 2009. J Antimicrob Chemoth 63: 7-10). Even when therapy has transformed this infection into a chronic disease rather than a fatal disease and also increased the life expectancy among patients to levels similar to those of the general population, it still represents unsolved serious problems which require the search for new strategies to decrease the used of antiretrovirals. That is the goal of the search for new therapeutic variants.
All the disadvantages of the available anti-HIV therapies support the need for new anti-HIV drugs differing mostly on their mechanisms and/or targets of action. An object of the invention is to provide a method to inhibit the replication and/or infection of the HIV. It is a further object of the invention to provide a method to inhibit the replication and/or infection of the HIV that has a different mechanism than inhibiting HIV polymerase or HIV protease. Another object of the invention is to provide a method to inhibit the replication and/or infection of the HIV by targeting the host cell and not the virus. Specifically, an object of the invention is to target the cytoskeleton, and more specifically the intermediate filaments (IFs) from the host cell. Specifically, another object of the invention is to target the host proteins vimentin and keratin-10. By targeting the host cell it is believed that it will be must more difficult for HIV to produce escape mutants. Vimentin and keratin-10 are important for the structure of the IFs and the present invention showed that they are a suitable target to inhibit HIV. Another object of the present invention is to provide agents and pharmaceutical compositions that disrupt the IFs of a cell or to decrease the amount of vimentin and/or keratin-10 host proteins.
At least one of the above mentioned objects is attained by the present invention.